Project Summary/Abstract In this project, we examine the role venous distention plays in the reflex regulation of blood pressure. Our prior work in humans demonstrates that vascular distension of peripheral limb veins evokes a powerful sympathoexcitatory reflex (venous distension reflex, VDR) that raises blood pressure. In this proposal, we have three specific aims: 1) we will determine the role played by cyclooxygenase metabolites of arachidonic acid in evoking the VDR, and examine how prostaglandins mediate their effects on the VDR in humans. Based on our supportive pilot data, we hypothesize that acute blockade of cyclooxygenase enzyme system will markedly attenuate muscle sympathetic nerve activity (MSNA) and arterial pressure responses to limb venous distention; 2) we will examine the hypothesis that limb venous distension increases the gain and resets the operating point of the baroreflex system in healthy subjects. We speculate that these changes in the gain and operating point of the baroreflex can buffer blood pressure changes during orthostatic challenge; We will also examine if the interaction between VDR and baroreflex differs in males and females; and 3) we will examine the role VDR plays in maintaining blood pressure during orthostatic stress in human subjects. We hypothesize that the strength of the VDR and/or the interaction between the VDR and the baroreflex will be related to orthostatic tolerance. We also hypothesize that individuals with ?orthostatic hypertension? will have a heightened VDR. We further speculate that maneuvers to reduce venous pooling in legs will attenuate the increase in blood pressure during orthostatic challenge in these subjects. The concepts to be studied challenge the prevailing ?conventional wisdom? regarding how blood pressure is regulated during orthostatic stress. If the proposed aims are achieved, we will gain insight into the mechanisms by which venous distension evokes sympathoexcitation, how the VDR interacts with the baroreflex, and how this reflex contributes to blood pressure control during orthostatic stress.